Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis

Abstract

Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure-response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG). Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229). One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized. Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed (free C5 < 0.5 μg/ml in 92% of patients; in vitro hemolysis < 20% in 87% of patients). Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of < 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range. Conclusions: Rigorous, quantitative, model-based exposure-response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing (900/1,200 mg) for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range.

Keywords: autoimmune; complement; eculizumab; exposure-response analysis; generalized myasthenia gravis; pharmacodynamics; pharmacokinetics.

Figure 1

Serum eculizumab concentrations during the study. Mean (95% CI) trough and peak serum eculizumab concentrations in patients who received eculizumab in the REGAIN study; eculizumab concentrations below the lower limit of quantification (9.38 μg/ml) were analyzed as 0 μg/ml. Eculizumab concentrations above 116 μg/ml (dashed line) indicate sufficient concentration to achieve complete complement inhibition (see Figure 3). CI, confidence interval.

Figure 2

Serum free C5 concentrations and complement-mediated hemolytic activity in serum during the study. (A) Mean (95% CI) serum free C5 concentrations. Free C5 concentrations below the lower limit of quantification (0.0274 μg/ml) were analyzed as 0.0137 μg/ml. Free C5 concentrations below 0.5 μg/ml (dashed line) indicate complete terminal complement inhibition. (B) Mean (95% CI) percent in vitro complement-mediated hemolytic activity of serum samples. Hemolysis values above 20% (dashed line) indicate incomplete inhibition of hemolysis. For both analyses, samples were taken before and after eculizumab infusion (i.e., at eculizumab serum trough and peak concentrations, respectively); samples taken before and after infusion in patients receiving placebo are shown for comparison. ^aSamples taken 5–90 min before infusion; ^bSamples taken 60 min after the completion of infusion; ^cDay 1. The numbers reported below the graphs are the numbers of patients for whom samples were tested at that timepoint. C5, complement protein 5; CI, confidence interval.

Figure 3

Target eculizumab concentration threshold providing complete complement inhibition (serum free C5 ≤ 0.5 μg/ml). Simulated exposure–response profile of free C5 concentration vs. eculizumab concentration, summarized using median response (gray solid line) and showing the 90% PI (gray shading). Using the threshold value 0.5 μg/ml, which is predicted to produce 20% hemolysis, the target concentration of eculizumab was identified as 116 μg/ml. C5, complement protein 5; PI, prediction interval.

Figure 4

Eculizumab exposure–response efficacy profiles for changes in (A) MG-ADL, (B) QMG, and (C) MGC total scores from baseline to Week 26. AUC, steady-state area under the concentration–time curve within the 2-week dosing interval; MG-ADL, Myasthenia Gravis-Activities of Daily Living; MGC, Myasthenia Gravis Composite; QMG, Quantitative Myasthenia Gravis evaluation.